Epilepsy is a widespread neurological disorder that affects 1-4% of the world's population. While many anti-epileptic drugs (AEDs) are available, approximately 25% of cases are non-responsive including cases associated with temporal lobe sclerosis and cortical malformations (CM). Thus, there is a tremendous need for additional research that focuses on the cause of seizure generation in these forms of epilepsy and potential therapeutic strategies. In both temporal lobe sclerosis and CM-related epilepsy, abnormal pro-convulsive circuits have been reported to occur in the dentate gyrus of the hippocampal formation and have been suggested to contribute to the generation of seizures. What we do not understand however, is why seizures occur only sporadically in these types of epilepsy, yet the aberrant pro-convulsive circuits are a permanent feature. This research project will focus on determining whether the presence of aberrant kainate receptors in these abnormal pro-convulsive circuits underlie their capacity to generate seizures sporadically. In this study, a combination of biochemical, anatomical and electrophysiological techniques and two models of epilepsy will be used to characterize the kainate receptors found in pro-convulsive circuits and to determine whether blocking or desensitizing them suppresses seizure generation during repetitive stimulation. If seizure generation can be suppressed, and the characteristics of these kainate receptors identified, new AEDs can be designed that specifically target kainate receptors in aberrant pro-convulsive circuits and thereby suppress seizure generation in patients afflicted with these types of epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy affects approximately 1-4% of the world's population with up to 25% of cases being unresponsive to currently available anti-epileptic drugs. Based on preliminary data this research project proposes to investigate whether aberrant kainate receptors contribute to the generation of seizures in epileptic tissue from models of temporal lobe sclerosis and cortical malformation-related epilepsy. This is a novel hypothesis regarding ictogenesis that should provide insight into a new therapeutic strategy for treating medically-intractable epilepsy. [unreadable] [unreadable] [unreadable] [unreadable]